Abstract Periodontitis is a prevalent chronic destructive inflammatory disease affecting tooth-supporting tissues in humans which may cause tooth loss. Approximately 35% of adults and 70% of senior population (>65 years old), globally, suffer from periodontal diseases. Currently, no ideal treatment is available for periodontitis. Local administration of antibiotics or anti-inflammatory drugs in different forms can reduce the bacterial infection but it cannot effectively alter progress of periodontium alveolar bone resorption and cannot positively promote the regeneration of periodontal tissue. Here, we will engineer microneedle-based drug delivery platforms for localized and prolonged treatment of periodontal disease by using an immunoengineering approach. Unlike the other products on market, our patches do not need adhesive or suture for sealing. Instead, the microneedles can self-detach from the dissolvable patch upon placement and stay in the gingival tissues for the course of treatment and degrade eventually. We hypothesize that (1) biodegradable microneedles allow effective and sustained and localized delivery of drugs in gingival tissues, and (2) immunoregulatory patches can modulate macrophage phenotype accelerate formation of regulatory T cells and thus inhibit periodontitis and gingivitis progress. (3) The sustained release of growth factor can also facilitate regeneration of periodontal tissue. Specifically, sustained and local co-delivery of immunoregulatory cytokines and growth factors can control the inflammation via formation of regulatory T cells as well as repolarizing pro-inflammatory macrophages toward anti-inflammatory macrophages that can accelerate regeneration of periodontal tissue. The engineered patch is biodegradable and possesses proper mechanical properties ensuring that material is easy to use in the clinical setting. The platform is modular and can load/deliver wide range of therapeutic proteins. To test our hypotheses, three Specific Aims are proposed: (1) To optimize a periodontal patch with detachable and biodegradable solid microneedles for prolonged delivery of nanoparticle-encapsulated antibiotic. (2) To optimize the engineered microneedle patch for co-delivery of immunoregulatory cytokines to reprogram host immune cells (e.g. inflammatory macrophages and T cells) toward anti-inflammatory, regulatory, and pro-healing lineages. (3) To evaluate the functionality of the engineered patches using a ligature-induced periodontal defect model in rats. Successful completion of this project will introduce a novel treatment platform for management of periodontitis, gingivitis and other periodontal diseases. Accomplishment of this project will advance our understanding of how localized alteration of immune system in periodontal environment can control and reverse the adverse effect of periodontitis. The long-term objective of this project is to translate the basic insights gained in this study into important and relevant clinical applications. This is a promising approach reduce inflammation as well as to promote tissue regeneration in periodontitis-related defects, and will have a significant impact on the therapy of periodontal diseases.